Arthritis Care & Research

Vol. 0, No. 0, Month 2019, pp 1–15

DOI 10.1002/acr.24025
© 2019, American College of Rheumatology. This article has been contributed to by US Government employees
and their work is in the public domain in the USA.

SPECIAL ARTICLE

2019 Update of the American College of Rheumatology/

Spondylitis Association of America/Spondyloarthritis
Research and Treatment Network Recommendations
for the Treatment of Ankylosing Spondylitis and
Nonradiographic Axial Spondyloarthritis
Michael M. Ward,1 Atul Deodhar,2 Lianne S. Gensler,3 Maureen Dubreuil,4 David Yu,5
Muhammad Asim Khan,6 Nigil Haroon,7 David Borenstein,8 Runsheng Wang,9 Ann Biehl,1 Meika A. Fang,10
11 12
Grant Louie, Vikas Majithia, Bernard Ng, Rosemary Bigham, Michael Pianin,15 Amit Aakash Shah,16
13 14

Nancy Sullivan, Marat Turgunbaev,16 Jeff Oristaglio,17 Amy Turner,16 Walter P. Maksymowych,18 and

17

Liron Caplan19

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to
provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence
to the recommendations within this guideline to be voluntary, with the ultimate determination regarding their application to be
made by the health care provider in light of each patient’s individual circumstances. Guidelines and recommendations are intended
to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations devel-
oped and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology,
and practice. ACR recommendations are not intended to dictate payment or insurance decisions. These recommendations cannot
adequately convey all uncertainties and nuances of patient care.

The American College of Rheumatology is an independent, professional, medical and scientific society that does not guarantee,
warrant, or endorse any commercial product or service.

Objective. To update evidence-­based recommendations for the treatment of patients with ankylosing spondylitis
(AS) and nonradiographic axial spondyloarthritis (SpA).
Methods. We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic
­treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-­to-­target
strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor
­necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading
of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and
formulate recommendations and required at least 70% agreement among the voting panel.
Results. Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over
­secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use
of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored
over tofacitinib. Co-­administration of low-­dose methotrexate with TNFi is not recommended, nor is a strict treat-­to-­target
strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only
for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis
magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radio-
graphs is not recommended.
Conclusion. These recommendations provide updated guidance regarding use of new medications and imaging
of the axial skeleton in the management of AS and nonradiographic axial SpA.

1
2       |
INTRODUCTION
Axial spondyloarthritis (SpA), comprising ankylosing spon-
dylitis (AS) and nonradiographic axial SpA, is the main form of
chronic inflammatory arthritis affecting the axial skeleton (1).
AS affects 0.1–0.5% of the population, and is characterized by
inflammatory back pain, radiographic sacroiliitis, excess spi-
nal bone formation, and a high prevalence of HLA–B27 (2,3).
Although nonradiographic axial SpA shares several features
with AS, advanced sacroiliac joint damage and spine ankylosis
are absent (4). The severity of arthralgia, stiffness, and limited
flexibility varies widely among patients and over the course of
axial SpA. Skeletal disease may be accompanied by uveitis,
psoriasis, and inflammatory bowel disease (IBD). Axial SpA can
impose substantial physical and social burdens on patients, and
can interfere with work and schooling (5,6). The goals of treat-
ment are to alleviate symptoms, improve functioning, maintain
the ability to work, decrease disease complications, and forestall
skeletal damage as much as possible.
In 2015, the American College of Rheumatology (ACR), Spon-
dylitis Association of America (SAA), and Spondyloarthritis Research
and Treatment Network (SPARTAN) published recommendations
for the treatment of adults with AS and those with nonradiographic
axial SpA (7). Recommendations were provided for pharmacologic
treatment, rehabilitation, use of surgery, management of selected
comorbidities, disease monitoring, patient education, and pre-
ventive care. The recommendations were tailored to patients with
either active or stable disease and focused on the most common
decisions confronting clinicians when treating these patients.
This article is published simultaneously in Arthritis & Rheumatology.
The views expressed herein do not necessarily represent those of the
National Institutes of Health or the United States Department of Veterans
Affairs.
Supported by the American College of Rheumatology, the Spondylitis
Association of America, and the Spondyloarthritis Research and Treatment
Network. Dr. Ward’s work was supported by the NIH (Intramural Research
Program grant ZIA-AR-041153 from the National Institute of Arthritis and
Musculoskeletal and Skin Diseases).
1
Michael M. Ward, MD, MPH, Ann Biehl, MS, PharmD, BCPS: National
Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda,
Maryland; 2Atul Deodhar, MD, MRCP: Oregon Health & Science University,
Portland; 3Lianne S. Gensler, MD: University of California, San Francisco;
4
Maureen Dubreuil, MD, MSc: Boston University School of Medicine,
Boston, Massachusetts; 5David Yu, MD: University of California, Los Angeles;
6
Muhammad Asim Khan, MD, FRCP, MACP: Case Western Reserve University,
Cleveland, Ohio; 7Nigil Haroon, MBBS, MD, DM: University of Toronto, Krembil
Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada;
8
David Borenstein, MD: Arthritis & Rheumatism Associates, Washington,
DC; 9Runsheng Wang, MD, MHS: Columbia University Medical Center, New
York, New York; 10Meika A. Fang, MD: VA West Los Angeles Medical Center,
Los Angeles, California; 11Grant Louie, MD, MHS: Arthritis and Rheumatism
Associates, Wheaton, Maryland; 12Vikas Majithia, MD, MPH: University
of Mississippi Medical Center, Jackson; 13Bernard Ng, MD: University of
Washington, Seattle; 14Rosemary Bigham: Seattle, Washington; 15Michael
Pianin, JD: Pianin and Associates, PC, Phoenix, Arizona; 16Amit Aakash Shah,
MD, MPH, Marat Turgunbaev, MD, MPH, Amy Turner: American College of
Rheumatology, Atlanta, Georgia; 17Nancy Sullivan, BA, Jeff Oristaglio, PhD:
ECRI Institute, Plymouth Meeting, Pennsylvania; 18Walter P. Maksymowych,
MD, FRCPC: University of Alberta, Edmonton, Alberta, Canada; 19Liron Caplan,
WARD ET AL
The advent of new medications to treat axial SpA war-
ranted this update. We did not reexamine all of the 2015 rec-
ommendations, but rather focused on those questions for
which consequential new evidence was present. We added
several new recommendations on how the newly available
medications should fit in treatment strategies and on the use
of imaging. The target populations are adults with AS or nonra-
diographic axial SpA. The target users of these recommenda-
tions are rheumatologists, primary care clinicians, physiatrists,
physical therapists, and others providing care to patients with
axial SpA.
METHODS
These recommendations followed ACR and Grading of
Recommendations, Assessment, Development and Evaluation
(GRADE) methodology (8,9), as described in Supplementary
Appendix 1, available on the Arthritis Care & Research web site at
http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract.
Briefly, sys­te­­matic literature reviews were done for prespecified
clinical population, intervention, comparator, outcomes (PICO)
questions. The resulting evidence was reviewed, and recom-
mendations formulated and voted on, by an expert voting panel
(see Supplementary Appendices 2–5 at http://onlin​elibr​ary.wiley.
com/doi/10.1002/acr.24025/​ abstract). Key definitions, includ-
ing ones for active and stable disease, are provided in Table 1.
Clinical t­rials of ixekizumab became available during the time the
­manuscript was in preparation, after the voting panel had met
(10,11). The data from these trials were provided to the voting
MD, PhD: Rocky Mountain Regional VA Medical Center and University of
Colorado, Aurora.
Dr. Deodhar has received consulting fees from AbbVie, Amgen,
Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Galapagos,
Janssen, and Pfizer (less than $10,000 each), Eli Lilly and Company, Novartis,
and UCB (more than $10,000 each). Dr. Gensler has received consulting
fees from AbbVie, Galapagos, Eli Lilly and Company, Novartis, Pfizer, and
UCB (less than $10,000 each). Dr. Khan has received consulting fees from
Eli Lilly and Company (less than $10,000), and AbbVie, and Novartis (more
than $10,000 each). Dr. Haroon has received consulting fees from Amgen,
AbbVie, Janssen, Eli Lilly and Company, Novartis, and UCB (less than $10,000
each). Dr. Borenstein has received consulting fees from AbbVie, Pfizer, and
Novartis (more than $10,000 each). Dr. Wang has received consulting fees
from Novartis and Eli Lilly and Company (less than $10,000 each), and had
no conflicts of interest during the time of guideline development, but before
publication became a consultant for Novartis, and a member of the medical
education advisory board for Eli Lilly. Dr. Louie has received consulting fees
from Janssen (less than $10,000). Dr. Majithia has received consulting fees
from Novartis (less than $10,000), and had no conflicts of interest during
the time of guideline development, but just before publication became the
site principal investigator for clinical trials for systemic lupus erythematosus
by Bristol-Myers Squibb and Janssen. Dr. Maksymowych has received
consulting fees from AbbVie, Boehringer, Celgene, Galapagos, Janssen, Eli
Lilly and Company, Novartis, Pfizer, and UCB (less than $10,000 each). No
other disclosures relevant to this article were reported.
Address correspondence to Michael M. Ward, MD, MPH, NIAMS/NIH,
Building 10 CRC, Room 4-1339, 10 Center Drive, MSC 1468, Bethesda, MD
20892. E-mail: wardm1@mail.nih.gov.
Submitted for publication March 28, 2019; accepted in revised form July
9, 2019.
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS |      3

Table 1.  Definitions of key terms*

Term
Active disease
Stable disease
Primary nonresponse
Secondary nonresponse
Conventional synthetic
antirheumatic drug
Biosimilar
TNFi
TNFi monoclonal antibodies
Biologics
High-­quality evidence
Moderate-­quality evidence
Low-­quality evidence
Very low-­quality evidence
Strong recommendation
Conditional recommendation
Patient preferences
Shared decision-­making
* TNFi = tumor necrosis factor inhibitor.
Definition
Disease causing symptoms at an unacceptably bothersome level to the patient and judged by the
examining clinician to be due to inflammation.
Disease that was asymptomatic or causing symptoms but at an acceptable level as reported by the
patient. A minimum of 6 months was required to qualify as clinically stable.
Absence of a clinically meaningful improvement in disease activity over the 3 to 6 months after
treatment initiation, not related to toxicity or poor adherence.
Recurrence of ankylosing spondylitis activity, not due to treatment interruption or poor adherence,
after having a sustained clinically meaningful improvement on treatment (generally, beyond the
initial 6 months of treatment).
Sulfasalazine, methotrexate, leflunomide, apremilast, thalidomide, pamidronate.
Biopharmaceuticals that are copies of an original biologic medication and tested to be of the same
purity and potency as the original. In these recommendations, we refer only to TNFi biosimilars.
Examples include infliximab-­d yyb, etanercept-­szzs, and adalimumab-­atto.
Infliximab, etanercept, adalimumab, certolizumab, golimumab, and their biosimilars.
Infliximab, adalimumab, certolizumab, golimumab.
TNFi, abatacept, rituximab, sarilumab, tocilizumab, ustekinumab.
Studies that provide high confidence in the effect estimate, and new data from future studies are
thought unlikely to change the effect.
Studies that provide confidence that the true effect is likely to be close to the estimate but could be
substantially different.
Studies that provide limited confidence about the effect, and the true effect may be substantially
different from the estimate.
Studies that provide very little certainty about the effect, and the true effect may be quite different
from the estimate.
Action should be favored in almost all patients, usually requiring high-quality evidence, high
confidence that future research will not alter the conclusion, AND an assessment that the desirable
effects of the intervention outweigh the undesirable effects. Should not be taken to imply that the
intervention has large clinical benefits.
Action should be followed in only selected cases, often limited by low-quality evidence, OR when the
desirable and undesirable consequences of an intervention are more balanced, OR if patients’
preferences for the intervention are thought to vary widely.
Beliefs and expectations regarding potential benefits and harms of treatment and how these relate to
an individual’s goals for health and life.
The process by which a patient and clinician arrive at an individualized treatment decision based on
an understanding of the potential benefits and risks of available treatment options and of a
patient’s values and preferences.

panel, and revised recommendations that included ixekizumab A. Recommendations for the treatment of
were reviewed and voted on by the panel. ­patients with active AS

In adults with active AS, we conditionally recommend

RESULTS
Here we present the recommendations that were reviewed in
this update, whether it was a new recommendation (designated
“new”) or reevaluation of an existing recommendation. Table  2
and Table  3 provide all current recommendations, i­ncluding
those from the 2015 report that were not newly reviewed. The
order of recommendations presented here does not imply pri-
ority for use or recommended sequencing of different interven-
tions. PICO numbers following each recommendation can be
used to locate related evidence in Supplementary Appendix 6,
available on the Arthritis Care & Research web site at http://
onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract.
continuous treatment with nonsteroidal antiinflammatory
drugs (NSAIDs) over on-demand treatment with NSAIDs
(PICO 1).
The efficacy of NSAIDs for symptom improvement in active
AS has been established in many controlled trials. Evidence that
continuous NSAID use results in slower rates of spinal fusion on
radiographs over 2 years compared to on-­demand NSAID use is
inconsistent, with results of one trial of celecoxib suggesting less
progression with continuous use, and one trial of diclofenac indicat-
ing no difference in progression (12,13) (See Supplementary Appen-
dix 6, available on the Arthritis Care & Research web site at http://
onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract). Despite the
4       | WARD ET AL

Table 2.  Recommendations for the treatment of adults with AS*

Level of
Recommendation evidence PICO
RECOMMENDATIONS FOR ADULTS WITH ACTIVE AS
1. We strongly recommend treatment with NSAIDs over no treatment with NSAIDs.† Low 2
2. We conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs. Low to 1
moderate
3. We do not recommend any particular NSAID as the preferred choice.† Low to 3
moderate
4. In adults with active AS despite treatment with NSAIDs, we conditionally recommend treatment with sulfasalazine, Very low to 7
methotrexate, or tofacitinib over no treatment with these medications. Sulfasalazine or methotrexate should be moderate
considered only in patients with prominent peripheral arthritis or when TNFi are not available.
5. In adults with active AS despite treatment with NSAIDs, we conditionally recommend treatment with TNFi over Very low 60
treatment with tofacitinib.
6. In adults with active AS despite treatment with NSAIDs, we strongly recommend treatment with TNFi over no High 6
treatment with TNFi.
7. We do not recommend any particular TNFi as the preferred choice. Moderate 5
8. In adults with active AS despite treatment with NSAIDs, we strongly recommend treatment with secukinumab or High 58
ixekizumab over no treatment with secukinumab or ixekizumab.
9. In adults with active AS despite treatment with NSAIDs, we conditionally recommend treatment with TNFi over Very low 59
treatment with secukinumab or ixekizumab.
10. In adults with active AS despite treatment with NSAIDs, we conditionally recommend treatment with secukinumab Very low 61
or ixekizumab over treatment with tofacitinib.
11. In adults with active AS despite treatment with NSAIDs and who have contraindications to TNFi, we conditionally Low 8
recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine, methotrexate, or
tofacitinib.
12. In adults with active AS despite treatment with the first TNFi used, we conditionally recommend treatment with Very low 10
secukinumab or ixekizumab over treatment with a different TNFi in patients with primary nonresponse to TNFi.
13. In adults with active AS despite treatment with the first TNFi used, we conditionally recommend treatment with a Very low 10
different TNFi over treatment with a non-­TNFi biologic in patients with secondary nonresponse to TNFi.
14. In adults with active AS despite treatment with the first TNFi used, we strongly recommend against switching to Very low 62
treatment with a biosimilar of the first TNFi.
15. In adults with active AS despite treatment with the first TNFi used, we conditionally recommend against the addi- Very low 9
tion of sulfasalazine or methotrexate in favor of treatment with a new biologic.
16. We strongly recommend against treatment with systemic glucocorticoids.† Very low 4
17. In adults with isolated active sacroiliitis despite treatment with NSAIDs, we conditionally recommend treatment Very low 13
with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.†
18. In adults with stable axial disease and active enthesitis despite treatment with NSAIDs, we conditionally recom- Very low 14
mend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocor-
ticoids. Peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided.†
19. In adults with stable axial disease and active peripheral arthritis despite treatment with NSAIDs, we conditionally Very low 15
recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local
glucocorticoids.†
20. We strongly recommend treatment with physical therapy over no treatment with physical therapy.† Moderate 16
21. W
 e conditionally recommend active physical therapy interventions (supervised exercise) over passive physical Very low 17
therapy interventions (massage, ultrasound, heat).†
22. We conditionally recommend land-based physical therapy interventions over aquatic therapy interventions.† Moderate 18
RECOMMENDATIONS FOR ADULTS WITH STABLE AS
23. We conditionally recommend on-demand treatment with NSAIDs over continuous treatment with NSAIDs. Low to 1
moderate
24. In adults receiving treatment with TNFi and NSAIDs, we conditionally recommend continuing treatment with TNFi Very low 11
alone compared to continuing both treatments.
25. In adults receiving treatment with TNFi and a conventional synthetic antirheumatic drug, we conditionally recom- Very low 12
mend continuing treatment with TNFi alone over continuing both treatments.
26. In adults receiving treatment with a biologic, we conditionally recommend against discontinuation of the biologic. Very low to 66
low

(Continued)
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS |      5

Table 2. (Cont’d)
Level of
Recommendation evidence PICO
27. In adults receiving treatment with a biologic, we conditionally recommend against tapering of the biologic dose as Very low to 65
a standard approach. low
28. In adults receiving treatment with an originator TNFi, we strongly recommend continuing treatment with the origi- Very low 63
nator TNFi over mandated switching to its biosimilar.
29. We strongly recommend treatment with physical therapy over no treatment with physical therapy.† Low 19
RECOMMENDATIONS FOR ADULTS WITH ACTIVE OR STABLE AS
30. In adults receiving treatment with TNFi, we conditionally recommend against co-­treatment with low-­dose metho- Low 64
trexate.
31. We conditionally recommend advising unsupervised back exercises.† Moderate 20
32. We conditionally recommend fall evaluation and counseling.† Very low 51
33. We conditionally recommend participation in formal group or individual self-management education.† Moderate 48
34. In adults with spinal fusion or advanced spinal osteoporosis, we strongly recommend against treatment with Very low 21
spinal manipulation.†
35. In adults with advanced hip arthritis, we strongly recommend treatment with total hip arthroplasty over no sur- Very low 25
gery.†
36. In adults with severe kyphosis, we conditionally recommend against elective spinal osteotomy.† Very low 26
RECOMMENDATIONS FOR ADULTS WITH AS-­RELATED COMORBIDITIES
37. In adults with acute iritis, we strongly recommend treatment by an ophthalmologist to decrease the severity, Very low 27
duration, or complications of episodes.†
38. In adults with recurrent iritis, we conditionally recommend prescription of topical glucocorticoids over no Very low 28
prescription for prompt at-home use in the event of eye symptoms to decrease the severity or duration of iritis
episodes.†
39. In adults with recurrent iritis, we conditionally recommend treatment with TNFi monoclonal antibodies over treat- Low 29
ment with other biologics.
40. In adults with inflammatory bowel disease, we do not recommend any particular NSAID as the preferred choice to Very low 31
decrease the risk of worsening of inflammatory bowel disease symptoms.†
41. In adults with inflammatory bowel disease, we conditionally recommend treatment with TNFi monoclonal antibod- Very low 32
ies over treatment with other biologics.
DISEASE ACTIVITY ASSESSMENT, IMAGING, AND SCREENING
42. W
 e conditionally recommend the regular-interval use and monitoring of a validated AS disease activity Very low 54
measure.†
43. W
 e conditionally recommend regular-interval use and monitoring of CRP concentrations or ESR over usual care Very low 55
without regular CRP or ESR monitoring.†
44. In adults with active AS, we conditionally recommend against using a treat-­to-­target strategy using a target of Low 67
ASDAS <1.3 (or 2.1) over a treatment strategy based on physician assessment.
45. We conditionally recommend screening for osteopenia/osteoporosis with DXA scan over no screening.† Very low 49
46. In adults with syndesmophytes or spinal fusion, we conditionally recommend screening for osteoporosis/osteo- Very low 50
penia with DXA scan of the spine as well as the hips, compared to DXA scan solely of the hip or other non-spine
sites.†
47. We strongly recommend against screening for cardiac conduction defects with electrocardiograms.† Very low 52
48. We strongly recommend against screening for valvular heart disease with echocardiograms.† Very low 53
49. In adults with AS of unclear activity while on a biologic, we conditionally recommend obtaining a spinal or pelvis Very low 68
MRI to assess activity.
50. In adults with stable AS, we conditionally recommend against obtaining a spinal or pelvis MRI to confirm inactivity. Very low 69
51. In adults with active or stable AS on any treatment, we conditionally recommend against obtaining repeat spine Very low 70
radiographs at a scheduled interval (e.g., every 2 years) as a standard approach.
* AS = ankylosing spondylitis; PICO = population, intervention, comparison, and outcomes; NSAIDs = nonsteroidal antiinflammatory drugs;
TNFi = tumor necrosis factor inhibitor; CRP = C-­reactive protein; ESR = erythrocyte sedimentation rate; ASDAS = Ankylosing Spondylitis Dis-
ease Activity Score; DXA = dual x-­ray absorptiometry; MRI = magnetic resonance imaging.
† These recommendations were from 2015 and were not reviewed in this update. The number preceding the recommendation is the recom-
mendation number and is referenced as bracketed numbers in Figure 1.
6       | WARD ET AL

Table 3.  Recommendations for the treatment of adults with nonradiographic axial SpA*
Level of
Recommendation evidence PICO
RECOMMENDATIONS FOR ADULTS WITH ACTIVE NONRADIOGRAPHIC AXIAL SpA
52. We strongly recommend treatment with NSAIDs over no treatment with NSAIDs.† Very low 34
53. We conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs. Very low 33
54. We do not recommend any particular NSAID as the preferred choice.† Very low 35
55. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treat- Very low 39
ment with sulfasalazine, methotrexate, or tofacitinib over no treatment with these medications.
56. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we strongly recommend treatment High 38
with TNFi over no treatment with TNFi.
57. We do not recommend any particular TNFi as the preferred choice. Very low 37
58. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treat- Very low 73
ment with TNFi over treatment with tofacitinib.
59. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treat- Very low 71
ment with secukinumab or ixekizumab over no treatment with secukinumab or ixekizumab.
60. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treat- Very low 72
ment with TNFi over treatment with secukinumab or ixekizumab.
61. In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treat- Very low 74
ment with secukinumab or ixekizumab over treatment with tofacitinib.
62. In adults with active nonradiographic axial SpA despite treatment with NSAIDs and who have contraindications to Very low 40
TNFi, we conditionally recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine,
methotrexate, or tofacitinib.
63. In adults with active nonradiographic axial SpA and primary nonresponse to the first TNFi used, we conditionally Very low 42
recommend switching to secukinumab or ixekizumab over switching to a different TNFi.
64. In adults with active nonradiographic axial SpA and secondary nonresponse to the first TNFi used, we conditionally Very low 42
recommend switching to a different TNFi over switching to a non-­TNFi biologic.
65. In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, we strongly recommend Very low 75
against switching to the biosimilar of the first TNFi.
66. In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, we conditionally recom- Very low 41
mend against the addition of sulfasalazine or methotrexate in favor of treatment with a different biologic.
67. We strongly recommend against treatment with systemic glucocorticoids.† Very low 36
68. In adults with isolated active sacroiliitis despite treatment with NSAIDs, we conditionally recommend treatment with Very low 45
local glucocorticoids over no treatment with local glucocorticoids.†
69. In adults with active enthesitis despite treatment with NSAIDs, we conditionally recommend using treatment with Very low 46
locally administered parenteral glucocorticoids over no treatment with local glucocorticoids. Peri-tendon injections
of Achilles, patellar, and quadriceps tendons should be avoided.†
70. In adults with active peripheral arthritis despite treatment with NSAIDs, we conditionally recommend using treat- Very low 47
ment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.†
71. We strongly recommend treatment with physical therapy over no treatment with physical therapy.† Low 22
72. W
 e conditionally recommend active physical therapy interventions (supervised exercise) over passive physical ther- Very low 23
apy interventions (massage, ultrasound, heat).†
73. We conditionally recommend land-based physical therapy interventions over aquatic therapy interventions.† Very low 24
RECOMMENDATIONS FOR ADULTS WITH STABLE NONRADIOGRAPHIC AXIAL SpA
74. We conditionally recommend on-­demand treatment with NSAIDs over continuous treatment with NSAIDs. Very low 33
75. In adults receiving treatment with TNFi and NSAIDs, we conditionally recommend continuing treatment with TNFi Very low 43
alone compared to continuing both medications.
76. In adults receiving treatment with TNFi and a conventional synthetic antirheumatic drug, we conditionally recom- Very low 44
mend continuing treatment with TNFi alone over continuing treatment with both medications.
77. In adults receiving treatment with a biologic, we conditionally recommend against discontinuation of the Low 79
biologic.
78. In adults receiving treatment with a biologic, we conditionally recommend against tapering of the biologic dose as a Very low 78
standard approach.
79. In adults receiving treatment with an originator TNFi, we strongly recommend continuation of treatment with the Very low 76
originator TNFi over mandated switching to its biosimilar.

(Continued)
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS |      7

Table 3. (Cont’d)
Level of
Recommendation evidence PICO
RECOMMENDATIONS FOR ADULTS WITH ACTIVE OR STABLE NONRADIOGRAPHIC AXIAL SpA
80. In adults receiving treatment with TNFi, we conditionally recommend against co-­treatment with low-­dose metho- Low 77
trexate.
DISEASE ACTIVITY ASSESSMENT AND IMAGING
81. W
 e conditionally recommend the regular-interval use and monitoring of a validated AS disease activity measure.† Very low 56
82. W
 e conditionally recommend regular-interval use and monitoring of the CRP concentrations or ESR over usual care Very low 57
without regular CRP or ESR monitoring.†
83. In adults with active nonradiographic axial SpA, we conditionally recommend against using a treat-­to-­target strategy Very low 80
using a target of ASDAS <1.3 (or 2.1) over a treatment strategy based on physician assessment.
84. In adults with nonradiographic axial SpA of unclear activity while on a biologic, we conditionally recommend obtain- Very low 81
ing a pelvis MRI to assess activity.
85. In adults with stable nonradiographic axial SpA, we conditionally recommend against obtaining a spinal or pelvis Very low 82
MRI to confirm inactivity.
86. In adults with active or stable nonradiographic axial SpA on any treatment, we conditionally recommend against Very low 83
obtaining repeat spine radiographs at a scheduled interval (e.g., every 2 years) as a standard approach.
* SpA = spondyloarthritis; PICO = population, intervention, comparison, and outcomes; NSAIDs = nonsteroidal antiinflammatory drugs; TNFi
= tumor necrosis factor inhibitor; AS = ankylosing spondylitis; CRP = C-­reactive protein; ESR = erythrocyte sedimentation rate; ASDAS = Anky-
losing Spondylitis Disease Activity Score; MRI = magnetic resonance imaging.
† These recommendations were from 2015 and were not reviewed in this update. The number preceding the recommendation is the recom-
mendation number and is referenced as bracketed numbers in Figure 1.

uncertainty regarding potential disease-­modifying effects, the com-
mittee conditionally favored continuous use of NSAIDs in patients
with active AS, primarily for controlling disease activity. The decision
to use NSAIDs continuously may vary depending on the severity of
symptoms, patient preferences, and comorbidities, particularly gas-
trointestinal and kidney comorbidities, and cardiovascular disease.
In adults with active AS despite treatment with NSAIDs, we
conditionally recommend treatment with sulfasalazine, metho-
trexate, or tofacitinib over no treatment with these medications
(new, PICO 7). Sulfasalazine or methotrexate should be consid-
ered only in patients with prominent peripheral arthritis or when
tumor necrosis factor inhibitors (TNFi) are not available.
Treatment with sulfasalazine is recommended primarily for
patients with prominent peripheral arthritis and few or no axial
symptoms. However, TNFi may provide a better option for these
patients. Evidence for the efficacy of sulfasalazine is based on 8
older controlled trials that showed benefit for peripheral arthritis
(see Supplementary Appendix 6, on the Arthritis Care & Research
web site at http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​
abstract). Although a recent placebo-­controlled trial of sulfasala-
zine demonstrated improvement in axial symptoms, and modest
clinical and imaging responses were seen in a second trial, the
preponderance of evidence indicates that sulfasalazine has lit-
tle benefit for axial symptoms (14,15). Sulfasalazine may have a
role in treating patients who have contraindications to TNFi, those
who decline treatment with TNFi, or those with limited access to
TNFi.
Three trials of methotrexate with negative results tested
doses of ≤10 mg weekly, and the lack of benefit may reflect
the low doses used (16–18). One uncontrolled study of meth-
otrexate 20 mg weekly showed no improvement in axial symp-
toms, but a decrease in swollen joint count (19). Treatment
with methotrexate may be considered for patients with pre-
dominately peripheral arthritis, although among nonbiologics,
there is more evidence supporting the use of sulfasalazine.
A phase II study of tofacitinib showed benefit in both clinical
and imaging outcomes of axial disease over 12 weeks (20). Use of
tofacitinib could be another option, although the results of phase
III trials are not available. Leflunomide, apremilast, thalidomide, and
pamidronate are not recommended (See Supplementary Appendix
6, available on the Arthritis Care & Research web site at http://onlin​e
libr​ary.wiley.com/doi/10.1002/acr.24025/​abstract).
In adults with active AS despite treatment with NSAIDs,
we strongly recommend treatment with TNFi over no treat-
ment with TNFi (PICO 6).
In adults with active AS despite treatment with NSAIDs,
we do not recommend any particular TNFi as the preferred
choice (PICO 5).
The efficacy of TNFi in patients with active AS has been
demonstrated in 24 randomized controlled trials, most of which
were short-­term (6 months or shorter) placebo-­controlled stud-
ies. Improvements were shown in patient-­reported outcomes,
composite response criteria, and spine and sacroiliac inflamma-
tion on magnetic resonance imaging (MRI) (see Supplementary
Appendix 6, on the Arthritis Care & Research web site at http://
onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract). The
panel judged that the evidence justified a strong recommenda-
8       |
tion for use of TNFi in patients whose AS remained active (as
defined in Table  1) despite treatment with NSAIDs. The panel
recommended that lack of response (or intolerance) to at least 2
different NSAIDs at maximal doses over 1 month, or incomplete
responses to at least 2 different NSAIDs over 2 months, would
be adequate trials with which to judge NSAID responsiveness
prior to escalating to treatment with TNFi.
Indirect comparisons in network meta-­analyses of clinical tri-
als have not showed clinically meaningful differences in short-­term
efficacy among TNFi in the treatment of active AS (see Supple-
mentary Appendix 6, at http://onlin​elibr​ary.wiley.com/doi/10.1002/
acr.24025/​abstract) (21). Direct comparisons among these medi-
cations are limited to a trial of infliximab versus its biosimilar, and a
very small open-­label trial of infliximab versus etanercept (22,23).
The panel judged that the evidence did not support preference of
1 TNFi over any other for the typical patient. Important exceptions
apply to patients with recurrent uveitis or coexistent IBD (see PICO
29 and PICO 32 below). Patients treated with infliximab may have
increased risks of tuberculosis and of infections generally (24,25).
TNFi other than infliximab should be considered for patients at
higher risk of tuberculosis exposure (either through travel or house-
hold contacts) or with a history of recurrent infections. Patient
preferences regarding the frequency of dosing and route of admin-
istration should be weighed when selecting a specific TNFi.
In adults with active AS despite treatment with NSAIDs,
we strongly recommend treatment with secukinumab or
ixekizumab over no treatment with secukinumab or ixeki-
zumab (new, PICO 58).
In adults with active AS despite treatment with NSAIDs,
we conditionally recommend treatment with TNFi over treat-
ment with secukinumab or ixekizumab (new, PICO 59).
In adults with active AS despite treatment with NSAIDs,
we conditionally recommend treatment with TNFi over treat-
ment with tofacitinib (new, PICO 60).
In adults with active AS despite treatment with NSAIDs,
we conditionally recommend treatment with secukinumab or
ixekizumab over treatment with tofacitinib (new, PICO 61).
The use of secukinumab and ixekizumab in patients with
active AS is supported by data from large placebo-­controlled trials
(see Supplementary Appendix 6, on the Arthritis Care & Research
web site at http://onlin​ elibr​
ary.wiley.com/doi/10.1002/acr.24025/​
abstract). The panel recommended use of TNFi over secukinumab
or ixekizumab based on greater experience with TNFi and familiarity
with their long-­term safety and toxicity. Similarly, the panel judged
that TNFi, secukinumab, or ixekizumab should be used over tofac-
itinib, given the larger evidence base for TNFi, secukinumab, and
ixekizumab. In patients with coexisting ulcerative colitis, if treatment
with TNFi is not an option, tofacitinib should be considered over
WARD ET AL
secukinumab or ixekizumab. Interleukin-17 (IL-17) inhibitors have
not been shown to be efficacious in IBD, although tofacitinib is an
approved treatment for ulcerative colitis (26,27).
In adults with active AS despite treatment with NSAIDs and
who have contraindications to TNFi, we conditionally recom-
mend treatment with secukinumab or ixekizumab over treatment
with sulfasalazine, methotrexate, or tofacitinib (new, PICO 8).
No studies have directly compared the risks and bene-
fits of treatment alternatives in patients who have contraindica-
tions to treatment with TNFi. The panel favored treatment with
secukinumab or ixekizumab over treatment with sulfasalazine or
methotrexate based on a higher likelihood of benefit, but this rec-
ommendation was conditional on the specific contraindication. If
the contraindication to TNFi use was the presence of congestive
heart failure or demyelinating disease, secukinumab or ixekizumab
was preferred, since these medications have not been shown to
worsen these conditions. If the contraindication to TNFi use was
tuberculosis, other chronic infection, or a high risk of recurrent
infections, sulfasalazine was preferred over secukinumab, ize-
kizumab, and tofacitinib. In these cases, efforts to mitigate the
infections should be undertaken so that TNFi might safely be
used. Treatment with rituximab, abatacept, ustekinumab, or IL-6
inhibitors is not recommended, even in patients with contraindi-
cations to TNFi, due to lack of effectiveness.
In adults with active AS despite treatment with the first
TNFi used, we conditionally recommend treatment with secuki-
numab or ixekizumab over treatment with a different TNFi in
patients with primary nonresponse to TNFi (new, PICO 10).
In adults with active AS despite treatment with the first
TNFi used, we conditionally recommend treatment with
a different TNFi over treatment with a non-TNFi biologic in
patients with secondary nonresponse to TNFi (new, PICO 10).
In adults with active AS despite treatment with the first
TNFi used, we strongly recommend against switching to
treatment with a biosimilar of the first TNFi (new, PICO 62).
In adults with active AS despite treatment with the first
TNFi used, we conditionally recommend against the addition
of sulfasalazine or methotrexate in favor of switching to a
new biologic (PICO 9).
Direct comparisons of treatment strategies for patients who
do not have or sustain adequate responses to their first TNFi have
not been reported, and the recommendations are based on the
panel’s consideration of indirect comparisons among the availa-
ble treatment options (see Supplementary Appendix 6, at http://
onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract). Data from
observational studies suggest that 25–40% of patients who switch
from one TNFi to another will have a meaningful response (e.g.,
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS
50% improvement in Bath AS Disease Activity Index) to the second
TNFi (28–30). However, not all patients in these studies switched
TNFi because of ineffectiveness.
The panel judged that treatment should differ for patients
who had a primary nonresponse to TNFi and those with second-
ary nonresponse to TNFi. Switching to secukinumab or ixeki-
zumab was recommended in most patients who had a primary
nonresponse to the first TNFi, under the assumption that TNF
was not the key inflammatory mediator in these patients. Con-
tinuing treatment with the first TNFi could be considered if addi-
tional time was believed important to assess the response fully,
or if a higher dose or shorter dosing interval was thought to be
beneficial.
In patients who relapse after an initial response (i.e., second-
ary nonresponse), the panel judged that treatment with a different
TNFi held a reasonable prospect of benefit and should be used
in most patients, rather than immediately switching to a different
class of biologics. Although ixekizumab is efficacious among TNFi
nonresponders, trials have not directly compared responses to
ixekizumab (or secukinumab) to responses to a second TNFi in
patients with a secondary nonresponse to the first TNFi (11). Given
that options for biologics are limited, treatment with a ­second TNFi
was recommended in these patients.
In cases of nonresponse (primary or secondary), the panel
recommended against switching to the biosimilar of the first TNFi
(e.g., switching from originator infliximab to infliximab-­dyyb), as
the clinical response would not be expected to be different. The
panel also recommended against the addition of sulfasalazine or
methotrexate to TNFi in cases of nonresponse to TNFi, judging
any benefit would likely be marginal. The addition of sulfasala-
zine could be considered in the rare patient whose axial symp-
toms are well-­controlled with TNFi but who has active peripheral
arthritis.
In adults with either active or stable AS on treatment with
TNFi, we conditionally recommend against co-treatment with
low-dose methotrexate (new, PICO 64).
In rheumatoid arthritis, the likelihood of TNFi discontinuation
is lower among patients who receive co-­treatment with methotrex-
ate, perhaps by reducing the development of antidrug antibodies
(31). In AS, it is less clear whether the duration of TNFi use, and
by inference their effectiveness, is similarly prolonged (32). Data
from observational studies are conflicting, although some studies,
primarily of infliximab, showed longer TNFi treatment when meth-
otrexate was co-­administered (see Supplementary Appendix 6
at http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract).
Clinical responses were not greater among patients who received
co-­treatment with methotrexate. In the absence of convincing evi-
dence of benefit, and due to greater burden for patients, the panel
recommended against routine co-­administration of methotrexate
with TNFi, although its use could be considered in patients treated
with infliximab.
|      9
B. Recommendations for the treatment of
­patients with stable AS
In adults with stable AS, we conditionally recommend
on-demand treatment with NSAIDs over continuous treat-
ment with NSAIDs (PICO 1).
This recommendation applies to patients whose AS has
been stable while not receiving any pharmacologic treatment.
In this group, the panel considered that the potential toxicities of
continuous NSAID treatment outweighed the uncertain benefit of
less radiographic progression. On-­demand treatment should be
considered for short-­term symptom recurrences (flares).
In adults with stable AS receiving treatment with TNFi
and NSAIDs, we conditionally recommend continuing treat-
ment with TNFi alone over continuing both medications
(PICO 11).
In adults with stable AS receiving treatment with TNFi
and a conventional synthetic antirheumatic drug, we con-
ditionally recommend continuing treatment with TNFi alone
over continuing both medications (PICO 12).
No new studies have directly compared outcomes between
patients who continued combination treatment and those who
discontinued either NSAIDs or a conventional synthetic antirheu-
matic drug (csARD). The NSAID-­sparing potential of etanercept
was demonstrated in a recent trial (33). The panel judged these
recommendations primarily based on symptom control, rather
than on any potential effect of combination therapy on future
spinal fusion. In stable patients, a trial of withdrawing either the
NSAIDs or the csARD should be considered, due to the likeli-
hood of greater toxicity with the long-­term use of more than one
medication. However, on-­demand NSAID treatment for control of
intermittent symptoms is recommended for patients with good
responses to previous courses of NSAIDs.
In adults with stable AS receiving treatment with a bio-
logic, we conditionally recommend against discontinuation
of the biologic (new, PICO 66).
In adults with stable AS receiving treatment with a bio-
logic, we conditionally recommend against tapering of the
biologic dose as a standard approach (new, PICO 65).
Data from several observational studies suggest that dis-
continuation of TNFi after achieving either remission or low
disease activity results in relapses in 60–74% of patients, occa-
sionally within a few weeks to months from discontinuation (see
Supplementary Appendix 6, available at http://onlin​ elibr​
ary.
wiley.com/doi/10.1002/acr.24025/​abstract). Although the data
only concerned TNFi discontinuation, the panel judged that a
similar recommendation would also apply to other biologics.
In general, treatment with a biologic should be planned to be
10       |
continued long-­term, barring toxicities. Discontinuation might be
considered in patients in sustained remission (i.e., several years),
with the anticipation that only one-­third of patients would not
experience relapse. Patient preferences should help guide this
decision.
Tapering of TNFi could entail a change in either the dose
or frequency of administration. Two controlled unblinded trials
of tapering etanercept to 25 mg weekly versus maintaining the
dose at 50 mg weekly in patients with stable AS showed that
remission or partial remission was somewhat less likely among
those in whom etanercept was tapered (34,35). In small obser-
vational studies, 53–70% of patients were still receiving their
reduced dose at 2 years, but there is little evidence regarding
maintenance of long-­term remission after tapering of TNFi (see
Supplementary Appendix 6, available at ttp://onlinelibrary.wiley.
com/doi/10.1002/acr.24025/abstract). Therefore, the panel
recommended against tapering of biologics as a standard
approach. One condition in which tapering could be considered
would be in patients with prolonged stable AS, if the patient and
provider engage in shared decision-­making.
In adults with stable AS receiving an originator TNFi, we
strongly recommend continuing treatment with the originator
TNFi over mandated switching to its biosimilar (new, PICO 63).
While the efficacy of originator and biosimilar TNFi is compara-
ble, and although either could be chosen to initiate new courses of
TNFi treatment, it was the opinion of the panel to recommend against
mandated switching to a biosimilar during the course of treatment,
in the absence of evidence of interchangability. Medication changes
can increase the risk of destabilizing a patient’s condition, and the
panel judged that additional data were needed to understand the
frequency of potential problems and concerns associated with
switching patients who were stable on an originator TNFi to its bio-
similar. Given these concerns, the panel judged that there should be
a compelling rationale for switching medications, particularly in light
of the marginal cost savings apparent for US patients (36).
C. Recommendations for adults with AS-­related
comorbidities
In adults with AS and recurrent uveitis, we conditionally
recommend treatment with TNFi monoclonal antibodies over
treatment with other biologics (PICO 29).
Evidence for this recommendation is limited to indirect com-
parisons of the rates of acute uveitis episodes in clinical trials or
observational studies, rather than from direct comparisons (see
Supplementary Appendix 6, available at http://onlin​elibr​ary.wiley.
com/doi/10.1002/acr.24025/​ abstract). Many reports showed
overall rates of uveitis without separately reporting recurrences as
opposed to incident episodes (37). The rates were generally lower
for adalimumab and infliximab compared to etanercept. For exam-
ple, a large observational study demonstrated rates of uveitis (per
WARD ET AL
100 patient-­ years) in patients receiving adalimumab, infliximab,
and etanercept of 13.6, 27.5, and 60.3, respectively, compared to
pretreatment rates of 36.8, 45.5, and 41.6, respectively (38). Adali-
mumab or infliximab are preferred over etanercept for the treatment
of AS in patients with recurrent uveitis. Certolizumab or golimumab
may also be considered, although supporting data are less sub-
stantial (39,40). Data from clinical trials suggest that rates of uvei-
tis flares were not different between patients with AS treated with
secukinumab and those treated with placebo, but more evidence
is needed. Secukinumab was not efficacious in the treatment of
panuveitis or posterior uveitis (41). Rates of uveitis flares among
patients treated with ixekizumab have not been well-­defined.
In adults with AS and IBD, we conditionally recommend
treatment with TNFi monoclonal antibodies over treatment
with other biologics (PICO 32).
This recommendation was based on limited indirect evi-
dence on the risks of flares or new onset of IBD among patients
with AS during treatment with biologics, and the much larger
literature on the treatment of IBD in general. Patients with AS
treated with infliximab or adalimumab have lower risks of IBD
exacerbations than those treated with etanercept (see Supple-
mentary Appendix 6, on the Arthritis Care & Research web site at
http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract).
Infliximab, adalimumab, and certolizumab are approved for the
treatment of Crohn’s disease, and infliximab, adalimumab, and
golimumab are approved for the treatment of ulcerative colitis,
while etanercept is not approved for either condition (42,43).
This evidence is the basis for the recommendation favoring
TNFi monoclonal antibody use in patients with AS and coexist-
ing IBD. The choice of the particular TNFi monoclonal antibody
should be made in consultation with the patient’s gastroenterol-
ogist. Secukinumab has been associated with the new onset, or
exacerbation, of Crohn’s disease (44–46). Increased risks of IBD
exacerbation appear to also occur with ixekizumab (47).
D. Recommendations for the treatment
of ­patients with either active or stable
­nonradiographic axial spondyloarthritis
Parallel questions on pharmacologic treatment were investi-
gated for patients with nonradiographic axial SpA. There were no
relevant published data for 19 questions. There was high-­quality
evidence only for the use of TNFi in nonradiographic axial SpA,
which was examined in several clinical trials. Low-­quality or very
low-­quality evidence from single studies suggested no differ-
ences in outcomes among different TNFi in nonradiographic axial
SpA, high likelihood of relapse following discontinuation of TNFi,
and no association between co-­treatment with nonbiologics and
TNFi persistence (see Supplementary Appendix 6, available at
http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​abstract).
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS
Therefore, the recommendations for nonradiographic axial SpA
were largely extrapolated from evidence in AS (Table 3). The rec-
ommendations were identical in both patient groups with 1 nota-
ble exception: treatment with secukinumab or ixekizumab was
strongly recommended over no treatment with secukinumab or
ixekizumab in patients with AS, while use of these medications
was conditionally recommended in patients with nonradiographic
axial SPA, because trials in nonradiographic axial SPA have not
been reported. Evidence on tofacitinib in nonradiographic axial
SpA has not been reported.
E. Disease activity assessment and imaging
In adults with active AS, we conditionally recommend
against using the treat-to-target strategy, which aims at a
target of an Ankylosing Spondylitis Disease Activity Score
<1.3 (or 2.1), over a treatment strategy based on physician
assessment (new, PICO 67).
The concept of treat-­to-­target strategies is well-­founded
in chronic disease management for conditions that have
an accurate measure of disease activity (often one that is
asymptomatic, as in blood pressure or glycosylated hemoglo-
bin), a tight link between this disease activity measure and future
health outcomes, and evidence that maintaining a particular tar-
get in the disease activity measure is closely associated with bet-
ter long-­term health (48). The treat-­to-­target approach in AS is
indirectly supported by associations between levels of AS activ-
ity and future radiographic progression but lacks robust direct
evidence. Because adoption of this strategy would place addi-
tional burdens on patients and providers, the panel judged that
more convincing evidence of benefit should be present before
endorsing this change in practice. There was also concern that
focus on a specific target could lead to rapid cycling through all
currently available treatments in some patients. As reflected in
the 2015 guidelines, quantifying disease activity is important to
help guide treatment decisions.
In adults with AS of unclear activity while receiving a
biologic, we conditionally recommend obtaining a spinal or
pelvis MRI to assess activity (new, PICO 68).
In adults with nonradiographic axial SpA of unclear
­ ctivity while receiving a biologic, we conditionally recom-
a SpA on any treatment, we conditionally recommend against
mend obtaining a pelvis MRI to assess activity (new, PICO 81).
Because physical and laboratory measures are often ­normal
despite active axial SpA, and because symptoms may be non-
specific, it may be difficult to know whether a patient is experi-
encing inflammation that warrants a change in treatment. Limited
evidence suggests that knowledge of MRI findings in the spine
and sacroiliac joints may alter treatment recommendations.
However, the degree of inflammatory change on MRI may not
correlate with treatment responses, and the location of inflam-
|      11
mation on MRI may not correlate with the location of pain (49)
(see Supplementary Appendix 6, available at http://onlin​elibr​ary.
wiley.com/doi/10.1002/acr.24025/​ abstract). The panel judged
that MRI could provide useful information in cases where the level
of disease activity was unclear and where this information would
influence treatment decisions. For patients with nonradiographic
axial SpA, the imaging should focus on the sacroiliac joints. In
interpreting MRI results, it is important to keep in mind the range
and frequency of abnormalities, including bone marrow edema
lesions, that may occur in individuals without axial SpA and that
may not represent inflammation due to axial SpA (50,51). MRI is
not recommended in patients in whom disease activity is either
clearly clinically active or clinically stable, or when the results of
MRI would not be expected to change treatment.
In adults with stable AS, we conditionally recommend
against obtaining a spinal or pelvis MRI to confirm inactivity
(new, PICO 69).
In adults with stable nonradiographic axial SpA, we con-
ditionally recommend against obtaining a spine or pelvis MRI
to confirm inactivity (new, PICO 82).
Because the clinical assessment of inflammation in
axial SpA has many limitations, questions may arise about
whether subclinical inflammation that could be detected by
MRI is being “missed” by either the physical examination,
symptoms, or laboratory studies. Given the lack of evidence
that obtaining an MRI in stable patients improves clinical
outcomes, the only moderate sensitivity and specificity of
MRI-­d efined abnormalities for measurement of activity in
axial SpA, the burden of testing, and concern for possible
overtreatment, the panel recommended against obtaining
an MRI in this setting. MRI could be considered in circum-
stances where the clinician and patient differ in their assess-
ment of whether the disease is stable.
In adults with active or stable AS receiving any treat-
ment, we conditionally recommend against obtaining repeat
spine radiographs at a scheduled interval (e.g., every 2 years)
as a standard approach (new, PICO 70).
In adults with active or stable nonradiographic axial
obtaining repeat spine radiographs at a scheduled interval
(e.g., every 2 years) as a standard approach (new, PICO 83).
Spine radiographs are useful for the diagnosis of axial SpA, in
evaluating the extent of spinal fusion, and for investigating new spi-
nal pain in patients with established AS. In research studies, small
changes in the extent of spine damage can be detected in 20–35% of
patients with AS over a 2-­year interval (see Supplementary Appendix
6, available at http://onlin​elibr​ary.wiley.com/doi/10.1002/acr.24025/​
abstract). There is no evidence that monitoring serial changes in
12       | WARD ET AL

Figure 1.  Summary of the main recommendations for the treatment of patients with A, active ankylosing spondylitis and B, stable ankylosing
spondylitis. AS = ankylosing spondylitis; NSAIDs = nonsteroidal antiinflammatory drugs; GC = glucocorticoid; SSZ = sulfasalazine; MTX =
methotrexate; LEF = leflunomide; APR = apremilast; THL = thalidomide; PAM = pamidronate; TNFi = tumor necrosis factor inhibitor; TOF =
tofacitinib; SEC = secukinumab; IXE = ixekizumab; IBD = inflammatory bowel disease; csARD = conventional synthetic antirheumatic drugs;
ESR = erythrocyte sedimentation rate; CRP = C-­reactive protein level; ASDAS = Ankylosing Spondylitis Disease Activity Score; MRI = magnetic
resonance imaging; PICO = population, intervention, comparison, and outcomes.
ACR/SAA/SPARTAN 2019 TREATMENT RECOMMENDATIONS IN AS
spine radiographs at a regular interval leads to better patient out-
comes, and data balancing a clinical benefit with the risk of radiation
exposure are absent. Therefore, the panel recommended against
repeating spine radiographs as a standard approach. In the absence
of clinical indications, repeat spine radiographs could be considered
on an ad hoc basis for counseling patients on the progression of
their disease, which may help in career and life planning.
F. Summary of recommendations
Figure  1 presents a diagram of the main treatment recom-
mendations for active and stable AS, integrating the new rec-
ommendations with the 2015 recommendations that were not
updated in this review.
DISCUSSION
This update was primarily motivated by the availability of new
treatment options, notably secukinumab, ixekizumab, tofacitinib,
and TNFi biosimilars, for patients with axial SpA. Providers and
patients have questions on where these new medications fit in the
pharmacologic strategy, and how originator TNFi, sulfasalazine,
and NSAIDs should be used given these new options. Based on
the current evidence and the considerations of the panel, NSAIDs
and TNFi remain the primary classes of medications for the treat-
ment of AS and nonradiographic axial SpA. Secukinumab or
ixekizumab is recommended for patients with active disease who
have heart failure or demyelinating disease as a contraindication
to TNFi, and in primary nonresponders to TNFi. Secukinumab and
ixekizumab are not recommended in patients with IBD or recurrent
uveitis, as TNFi monoclonal antibodies are better options. Tofac-
itinib is a potential second-­line option for patients with contraindi-
cations to TNFi other than infections. Recommendations regarding
tofacitinib may change pending the results of larger clinical trials.
Several of the 2015 recommendations were modified in this
update. The current recommendation is conditionally in favor of
use of sulfasalazine in limited clinical circumstances, whereas the
2015 recommendations had this as an exception to the general
recommendation against the use of conventional synthetic anti-
rheumatic drugs. In the 2015 recommendations, sulfasalazine
and pamidronate were suggested as alternatives for the treat-
ment of patients with active disease and contraindications to
TNFi, while the current recommendations suggest use of secuki-
numab or ixekizumab in most of these cases (except patients
with high risk of infections). In cases of failure of TNFi, the 2015
guidelines included a conditional recommendation for a trial of
a second TNFi and against use of a non-­TNFi biologic, whereas
the current guidelines differentiate treatment recommendations
based on whether there was primary or secondary nonresponse
to the TNFi. For the treatment of patients with recurrent uveitis,
the previous guidelines specified conditional use of infliximab or
adalimumab, while the update broadened this recommendation
|      13
to include TNFi monoclonal antibodies generally. Similarly, for
patients with coexisting IBD, the update includes a conditional
recommendation for TNFi monoclonal antibodies over other bio-
logics, rather than over only etanercept. Finally, the recommen-
dation for use of TNFi in patients with active nonradiographic
axial SpA was changed from conditional to strong.
New questions on the treatment of patients with stable
disease were addressed in this update. Discontinuation of bio-
logics is not recommended due to the likelihood for symptom
recurrence. If tapering is considered, patients should be coun-
seled regarding the potential for increased disease activity.
Co-­treatment with low-­dose methotrexate is not generally rec-
ommended, but ongoing studies will shed further light on this
question. Switching to a biosimilar during the course of treat-
ment with TNFi is also not recommended, echoing the concerns
previously expressed by the ACR (52).
Imaging remains a central tool in the diagnosis of axial
SpA, but its role in monitoring patients is less well-­defined.
Spine and/or pelvis MRI could aid in the evaluation of patients
in whom the degree of active inflammation is uncertain, and
especially in those for whom the findings would change man-
agement. MRI is not recommended to seek subclinical inflam-
mation in patients with stable disease (as defined in Table 1).
However, MRI could be considered in circumstances where it
may inform shared decision-­making. We recommend against
obtaining spine radiographs on scheduled intervals to monitor
progression. This practice entails radiation exposure and would
not alter treatment in most cases.
We used the GRADE method to develop these treatment
recommendations in a way that was transparent, systematic,
and explicit, and that was informed by the medical evidence as
well as patient preferences. The major limitation of these guide-
lines is the very low quality of evidence for many recommenda-
tions, which necessitated reliance on the clinical expertise of the
panel. For nonradiographic axial SpA, most recommendations
were based on extrapolation of results from studies in AS. We
tried to identify the most common and consequential treatment
questions, so that the recommendations would be useful in
guiding clinical decision-­making. The low quality of evidence for
many questions is an indication that research has not yet tack-
led many of the most important treatment questions. As more
treatment options become available, this problem will grow.
Importantly, failure to recommend a particular medication does
not imply that it is contraindicated. Key evidence gaps include
the comparative effectiveness and safety of different biologics,
the optimal sequencing of treatments, and the role of NSAIDs.
This update addressed only a subset of treatment ques-
tions. The 2015 recommendations that were not reexamined
are to be considered extant. Recommendations are meant to
describe the approach to treatment of the typical patient and
cannot anticipate all possible clinical scenarios. Application of
these recommendations must be individualized, and requires
14       |
careful assessment, sound clinical judgment of each patient’s
circumstances, and consideration of a patient’s preferences.
ACKNOWLEDGMENTS
We thank Cassie Shafer and Elin Aslanyan of the SAA for
their partnership on this project. We thank SPARTAN for its part-
nership on this project. We thank our patient representatives for
adding valuable perspectives. We thank the ACR staff, includ-
11.
ing Ms Regina Parker for assistance in organizing the face-­to-­
face meeting and coordinating the administrative aspects of
the project, and Ms Robin Lane for assistance in manuscript
preparation. We thank Ms Janet Waters for help in developing
the literature search strategy and performing the literature search
and updates, and Ms Janet Joyce for peer-­reviewing the litera-
ture search strategy.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically
for important intellectual content, and all authors approved the final ver-
sion to be published. Dr. Ward had full access to all of the data in the
study and takes responsibility for the integrity of the data and the accu-
racy of the data analysis.
Study conception and design. Ward, Deodhar, Turner, Caplan.
Acquisition of data. Ward, Deodhar, Shah, Sullivan, Turgunbaev,
Oristaglio, Caplan.
Analysis and interpretation of data. Ward, Deodhar, Gensler, Dubreuil, Yu,
Khan, Haroon, Borenstein, Wang, Biehl, Fang, Louie, Majithia, Ng, Bigham,
Pianin, Shah, Sullivan, Turgunbaev, Oristaglio, Maksymowych, Caplan.
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